The benzopyran-4-one derivative compound of formula I has a flavonoid moiety, which previously isolated and identified from the whole plant extract of Thelypteris torresiana, a fern species native to Taiwan.
The exposure and biological effects of Protoapigenone (I-1), 5′,6′-Dihydro-6′-methoxy-protoapigenone (I-2) and Protoapigenin (I-3) compounds have been investigated by cytotoxicity assay. It was found Protoapigenone (I-1) demonstrated therapeutic effects and was a lead compound for potential anticancer drug development.

Furthermore, for developing a new potent anticancer drug, several analogues of I type compound such as I-4, I-5, I-6, I-7 and I-8, and another II type moiety such as II-1 and II-2 compound are also synthesized or semi-synthesized. Where the compound I-4 having chemical name 2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)-4H-chromen-4-one can be expressed by the general names of protoflavonone. The compound I-5 is also termed as 5-hydroxyprotoflavone, whose chemical name is 2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)-5-hydroxy-4H-chromen-4-one. The compound I-6 having chemical name 5-hydroxy-2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)-7-methoxy-4H-chromen-4-one can be expressed by the general names of 5-hydroxy-7-methoxy-protoflavonone. The homologous compounds I-4 and I-7 have the similar structure, but a different function group on R11 positions only, which is a hydroxyl group and another is methoxyl group in that position. The compound I-5, I-8, II-1 and II-2 also present the modified function group of R11 positions models.

Formula II having an β-naphthoflavone moiety, the compound II-1 has chemical name 3-(1-hydroxy-4-oxo-cyclohexa-2,5-dienyl)-1H-benzo[f]chromen-1-one. Compound II-2 has chemical name 1′-methoxy-β-naphthoflavone.

In previous studies, Protoapigenone (I-1) and its more potent analog compound II-1 (FIG. 1A) were shown to induce oxidative stress, consequently activating the p38 and JNK1/2 MAPK pathways following cell cycle arrest and apoptosis in several cancer cell types. These compounds were also found to reduce the size of tumor xenografts in nude mice without exerting toxic effects on the recipient. Recently, in those compounds of formula I and II were found to induce chromosomal breakage through oxidative stress, implicating a role for benzopyran-4-one derivatives of formula I and II in interfering with DNA metabolism. Up to date, the biomolecular actions and implications of this benzopyran-4-one derivatives mediated interference are mostly undetermined. Herein, we found that benzopyran-4-one derivatives are capable of inhibiting DNA damage-induced activation of ATR targets Chk (Cell Cycle Checkpoint Kinase) 1 and FANCD2, which then sensitize tumor cells to chemotherapy, and finally results in tumor size reduction in mice.
During virus infection, the immune system of the host is typically activated for defense. However, once it enters into a host cell, the virus will exploit some of the host cell's machinery to replicate themselves at high speed. Several types of viruses have shown this replication, including the DNA viruses Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), adenovirus and SV40, papilloma virus, Hepatitis B virus, sindbis virus, and the lentivirus human immunodeficiency virus (HIV), which lead to the activation of host DNA-damage response pathways. The activation of cellular DNA repair and recombination enzymes is beneficial for viral replications. Further, research shows that new small-molecule inhibitors of the DNA-damage response pathways may be of value to treat viral infections.
Strategies for identifying targets for antiviral intervention typically focus on compounds that attack the viral proteins including the structural components of the virion as well as viral genome-encoded enzymes which are necessary for propagation of the virus. The approach of targeting viral proteins has several limitations: i) the limited number of viral targets; ii) viral targets tend to be highly specific to a particular virus or even strain of virus; and iii) viruses are able to rapidly alter their genetic composition to develop resistance to antiviral drugs. Another approach in antiviral drug development is to design drugs to strengthen the host's factors to fight the viral infection, rather than to fight the viral infection itself.
Our results show that these benzopyran-4-one derivatives compounds are noteworthy potential to treat virus infection by the inhibition of ATR signaling cascades.